Pyridyl-2-methylamino compounds, compositions and uses thereof

ABSTRACT

Compounds are provided according to formula I: 
                         
where R, R′, R 3 , R 4 , R 5 , and R 6  are as defined herein. Provided compounds and pharmaceutical compositions thereof are useful for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, Alzheimer&#39;s Disease, Down&#39;s syndrome, Parkinson&#39;s Disease, and others.

RELATED APPLICATION

The present application claims the benefit under 35 U.S.C. §119 of U.S.Provisional Application Ser. No. 61/505,511, filed Jul. 7, 2011. Thecontent of said provisional application is hereby incorporated byreference in its entirety.

FIELD

Provided herein are pyridylmethylamine compounds with anti-Aβproduction, aggregation, inhibition of oxidative stress, and modulationof amyloid precursor protein (APP) translation properties, andpharmaceutical compositions thereof. Also provided are methods forpreventing and/or treating medical conditions in mammals, such asneurodegenerative diseases including Alzheimer's, using the compoundsand pharmaceutical compositions provided herein.

BACKGROUND

Pathogenesis of Alzheimer's disease (AD) is associated with accumulationof a hydrophobic β-amyloid (Aβ) peptide in the brain, which readilyself-assembles into toxic oligomers and insoluble fibrils. Aβ oligomersare particularly destructive to excitatory synapses in the hippocampusas they bind to N-methyl-D-aspartic acid (NMDA) receptor proteins andcause their down regulation along with causing profound disturbances insynaptic morphology. In turn, Aβ fibrils form Aβ plaques, which areassociated with deleterious activation of microglia and dystrophy ofneurites passing along their vicinity. Long-term buildup of Aβ in thebrain results in neurodegenerative cascade leading to widespreadsynaptic degeneration, formation of neurofibrillary tangles randneuronal death resulting in occurrence of dementia in AD patients.Therefore, strategies modulating production, clearance andself-aggregation of Aβ are actively being pursued as disease modifyingtherapies.

Various agents can be used to treat medical conditions associated withAD.

However, despite the broad range of biological activities, the use ofthese agents has been limited by their toxicity at higher dose and lackof sufficient therapeutic efficacy at lower dose.

Thus, there remains a need to make new compounds which can havetherapeutic efficacy for various neurodegenerative diseases includingAD. The compounds, compositions, and methods described herein aredirected toward this end.

SUMMARY OF THE INVENTION

In certain aspects, provided herein are pyridylmethylamine compoundswith anti-Aβ production, aggregation, inhibition of oxidative stress,and modulation of amyloid precursor protein (APP) translationproperties, and pharmaceutical compositions thereof. Also provided aremethods for preventing and/or treating medical conditions in mammals,such as neurodegenerative diseases including Alzheimer's, using thecompounds and pharmaceutical compositions provided herein.

In certain aspects, provided herein are pyridylmethylamine compoundsuseful for preventing and/or treating a broad range of neurodegenerativeconditions, such as AD, Down's syndrome, Parkinson's and others.

In another aspect, provided here are methods for preventing, treating orameliorating in a mammal various medical conditions, such asneurodegenerative conditions, which comprises administering to themammal an effective medical condition treating amount of apyridylmethylamine compound.

In one specific aspect, provided herein are method for preventing,treating or ameliorating in a mammal a medical condition, such asneurodegenerative conditions, which comprises administering to themammal an effective medical condition treating amount of a compoundaccording to formula I:

or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or acombination thereof;wherein:

-   -   R₃, R₄, R₅ and R₆ are independently selected from the group        consisting of hydrogen, halogen, substituted or unsubstituted        C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,        substituted or unsubstituted C₂₋₈ alkynyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted heterocyclyl, halogen,        trihalomethyl, —CN, —NO₂, —NH₂, —OR₁, —NR₁R₂, —S(O)₀₋₂R₁,        —SO₂NR₁R₂, —CO₂R₁, —C(O)NR₁R₂, —N(R₁)SO₂R₂, —C(O)R₁,        —N(R₂)C(O)R₂, —N(R₁)CO₂R₂, —OC(O)NR₁R₂, —OC(O)R₁, and optionally        substituted lower alkyl;    -   R₁ and R₂ are independently selected from the group consisting        of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,        substituted or unsubstituted C₂₋₈ alkenyl, substituted or        unsubstituted C₂₋₈ alkynyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, substituted or        unsubstituted heterocyclyl, and optionally substituted lower        alkyl;    -   R is selected from the group consisting of hydrogen, substituted        or unsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈        alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, substituted        or unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted heterocyclyl, —S(O)₀₋₂R₁,        —SO₂NR₁R₂, —CO₂R₁, —C(O)NR₁R₂, —N(R₁)SO₂R₂, —N(R₁)C(O)R₂,        —N(R₁)CO₂R₂, —C(O)R₁, and optionally substituted lower alkyl;    -   R′ is selected from the group having formula II:

-   -   wherein    -   the subscript m is 1, 2, 3, or 4; the subscript n is 0, 1, 2, or        3;    -   R′″ is selected from the group consisting of hydrogen, halogen,        substituted or unsubstituted C₁₋₈ alkyl, substituted or        unsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈        alkynyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heterocyclyl, halogen, trihalomethyl, —CN, —NO₂, —NH₂, —OR₁,        —NR₁R₂, —S(O)₀₋₂R₁, —SO₂NR₁R₂, —CO₂R₁, —C(O)NR₁R₂, —N(R₁)SO₂R₂,        —C(O)R₁, —N(R₁)C(O)R₂, —N(R₁)CO₂R₂, OC(O)NR₁R₂, —OC(O)R₁, and        optionally substituted lower alkyl;    -   R″ is H or substituted or unsubstituted C₁₋₈ alkyl or        substituted or unsubstituted C₂₋₈ alkenyl, substituted or        unsubstituted C₂₋₈ alkynyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, substituted or        unsubstituted heterocyclyl, trihalomethyl, or selected from the        group having formula III:

wherein

-   -   R_(a) is selected from the group consisting of hydrogen,        halogen, substituted or unsubstituted C₁₋₈ alkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl

In one embodiment, with respect to the method, the medical condition isAD.

In other embodiment, the medical condition is Down's syndrome.

In other embodiment, the medical condition is Parkinson's disease.

In another specific aspect, provided herein are pharmaceuticalcompositions for preventing, treating or ameliorating in a mammal amedical condition, such as neurodegenerative conditions, which comprisesa compound according to formula I:

or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or acombination thereof;wherein R, R′, R₃, R₄, R₅, and R₆ are as described above.

In a specific aspect, provided herein is a pharmaceutical composition ofa compound according to formula V:

or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or acombination thereof.

The present invention further provides a method of treating a disease ina patient, where the disease is associated AD, by administering to thepatient a therapeutically effective amount of a compound of formula I.

Other objects and advantages will become apparent to those skilled inthe art from a consideration of the ensuing detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 presents a series of assays demonstrating the activity ofcompounds of the invention. FIG. 1(A) is a Thioflavin T fibrillizationassay; FIG. 1(B) presents the results of TEM analysis; FIG. 1(C) showsthe results of an oligomerization assay, FIG. 1(D) presents theprinciple of the assay; and FIG. 1(E) presents the results of a TEMassay.

FIG. 2 presents the results of an MTT assay, to assess the viability ofcells grown in the presence of compounds of the invention.

FIGS. 3A-3D demonstrate the results of incubation of the compounds ofthe invention with CHO clones transfected with WT human APP751 anddouble Swedish APP751 mutants.

FIGS. 4(A) and 4(B) present the results of ex-vivo tests of thecompounds to assess their effect on the viability of oxidativelychallenged neural cells.

FIGS. 5(A)-5(C) present the results of the testing of APP_(SW)/PS1_(dE9) AD Tg mice to assess the effect of compounds of the invention onviability and memory deficit.

FIGS. 6(A)-6(F) present the results of the presence of compounds of theinvention on the accumulation of Aβ brain plaques.

FIGS. 7(A)-7(D) present the results of tests that demonstrate that thecompounds of the invention do not appear to modulate APP secretaseactivity.

FIGS. 8(A)-8(C) present results that illustrate the effect of thecompounds of the invention on APP translation.

DEFINITIONS

Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed inside cover, and specificfunctional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The invention additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The following terms are intended to have the meanings presentedtherewith below and are useful in understanding the description andintended scope of the present invention. When describing the invention,which may include compounds, pharmaceutical compositions containing suchcompounds and methods of using such compounds and compositions, thefollowing terms, if present, have the following meanings unlessotherwise indicated. It should also be understood that when describedherein any of the moieties defined forth below may be substituted with avariety of substituents, and that the respective definitions areintended to include such substituted moieties within their scope as setout below. Unless otherwise stated, the term “substituted” is to bedefined as set out below. It should be further understood that the terms“groups” and “radicals” can be considered interchangeable when usedherein. The articles “a” and “an” may be used herein to refer to one orto more than one (i.e. at least one) of the grammatical objects of thearticle. By way of example “an analogue” means one analogue or more thanone analogue.

“Alkyl” refers to a radical of a straight-chain or branched saturatedhydrocarbon group having from 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). Insome embodiments, an alkyl group has 1 to 12 carbon atoms (“C₁₋₁₂alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms(“C₁₋₁₀ alkyl”). In some embodiments, an alkyl group has 1 to 9 carbonatoms (“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8carbon atoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1to 7 carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl grouphas 1 to 6 carbon atoms (“C₁₋₆ alkyl”, also referred to herein as “loweralkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms(“C₁₋₅ alkyl”). In some embodiments, an alkyl group has 1 to 4 carbonatoms (“C₁₋₄ alkyl”). In some embodiments, an alkyl group has 1 to 3carbon atoms (“C₁₋₃ alkyl”). In some embodiments, an alkyl group has 1to 2 carbon atoms (“C₁₋₂ alkyl”). In some embodiments, an alkyl grouphas 1 carbon atom (“C₁ alkyl”). In some embodiments, an alkyl group has2 to 6 carbon atoms (“C₂₋₆ alkyl”). Examples of C₁₋₆ alkyl groupsinclude methyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl(C₄), tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅),3-pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅),tertiary amyl (C₅), and n-hexyl (C₆). Additional examples of alkylgroups include n-heptyl (C₇), n-octyl (C_(s)) and the like. Unlessotherwise specified, each instance of an alkyl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents;e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1substituent. In certain embodiments, the alkyl group is unsubstitutedC₁₋₁₀ alkyl (e.g., —CH₃). In certain embodiments, the alkyl group issubstituted C₁₋₁₀ alkyl.

“Alkylene” refers to a substituted or unsubstituted alkyl group, asdefined above, wherein two hydrogens are removed to provide a divalentradical. Exemplary divalent alkylene groups include, but are not limitedto, methylene (—CH₂—), ethylene (—CH₂CH₂—), the propylene isomers (e.g.,—CH₂CH₂CH₂— and —CH(CH₃)CH₂—) and the like.

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds, and no triple bonds (“C₂₋₂₀ alkenyl”). Insome embodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents e.g., for instancefrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Incertain embodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl.In certain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl.

“Alkenylene” refers a substituted or unsubstituted alkenyl group, asdefined above, wherein two hydrogens are removed to provide a divalentradical. Exemplary divalent alkenylene groups include, but are notlimited to, ethenylene (—CH═CH—), propenylenes (e.g., —CH═CHCH₂— and—C(CH₃)═CH— and —CH═C(CH₃)—) and the like.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds, and optionally one or more double bonds(“C₂₋₂₀ alkynyl”). In some embodiments, an alkynyl group has 2 to 10carbon atoms (“C₂₋₁₀ alkynyl”). In some embodiments, an alkynyl grouphas 2 to 9 carbon atoms (“C₂₋₉ alkynyl”). In some embodiments, analkynyl group has 2 to 8 carbon atoms (“C₂₋₈ alkynyl”). In someembodiments, an alkynyl group has 2 to 7 carbon atoms (“C₂₋₇ alkynyl”).In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C₂₋₆alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms(“C₂₋₅ alkynyl”). In some embodiments, an alkynyl group has 2 to 4carbon atoms (“C₂₋₄ alkynyl”). In some embodiments, an alkynyl group has2 to 3 carbon atoms (“C₂₋₃ alkynyl”). In some embodiments, an alkynylgroup has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon-carbontriple bonds can be internal (such as in 2-butynyl) or terminal (such asin 1-butynyl). Examples of C₂₋₄ alkynyl groups include, withoutlimitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl(C₄), 2-butynyl (C₄), and the like. Examples of C₂₋₆ alkenyl groupsinclude the aforementioned C₂₋₄ alkynyl groups as well as pentynyl (C₅),hexynyl (C₆), and the like. Additional examples of alkynyl includeheptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified,each instance of an alkynyl group is independently optionallysubstituted, i.e., unsubstituted (an “unsubstituted alkynyl”) orsubstituted (a “substituted alkynyl”) with one or more substituents;e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1substituent. In certain embodiments, the alkynyl group is unsubstitutedC₂₋₁₀ alkynyl. In certain embodiments, the alkynyl group is substitutedC₂₋₁₀ alkynyl.

“Alkynylene” refers a substituted or unsubstituted alkynyl group, asdefined above, wherein two hydrogens are removed to provide a divalentradical. Exemplary divalent alkynylene groups include, but are notlimited to, ethynylene, propynylene, and the like.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14πelectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Typicalaryl groups include, but are not limited to, groups derived fromaceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexalene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, andtrinaphthalene. Particularly aryl groups include phenyl, naphthyl,indenyl, and tetrahydronaphthyl. Unless otherwise specified, eachinstance of an aryl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted aryl”) or substituted (a “substitutedaryl”) with one or more substituents. In certain embodiments, the arylgroup is unsubstituted C₆₋₁₄ aryl. In certain embodiments, the arylgroup is substituted C₆₋₁₄ aryl.

In certain embodiments, an aryl group substituted with one or more ofgroups selected from halo, C₁-C₈ alkyl, C₁-C₈ haloalkyl, cyano, hydroxy,C₁-C₈ alkoxy, and amino.

Examples of representative substituted aryls include the following

In these formulae one of R⁵⁶ and R⁵⁷ may be hydrogen and at least one ofR⁵⁶ and R⁵⁷ is each independently selected from C₁-C₈ alkyl, C₁-C₈haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C₁-C₈ alkoxy,heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR⁵⁸COR⁵⁹,NR⁵⁸SOR⁵⁹NR⁵⁸SO₂R⁵⁹, COOalkyl, COOaryl, CONR⁵⁸R⁵⁹, CONR⁵⁸OR⁵⁹, NR⁵⁸R⁵⁹,SO₂NR⁵⁸R⁵⁹, S-alkyl, SOalkyl, SO₂alkyl, Saryl, SOaryl, SO₂aryl; or R⁵⁶and R⁵⁷ may be joined to form a cyclic ring (saturated or unsaturated)from 5 to 8 atoms, optionally containing one or more heteroatomsselected from the group N, O, or S. R⁶⁰ and R⁶¹ are independentlyhydrogen, C₁-C₈ alkyl, C₁-C₄ haloalkyl, C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, substituted C₆-C₁₀ aryl, 5-10 memberedheteroaryl, or substituted 5-10 membered heteroaryl.

“Fused aryl” refers to an aryl having two of its ring carbon in commonwith a second aryl ring or with an aliphatic ring.

“Aralkyl” is a subset of alkyl and aryl, as defined herein, and refersto an optionally substituted alkyl group substituted by an optionallysubstituted aryl group.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10π electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing threeheteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containingtwo heteroatoms include, without limitation, pyridazinyl, pyrimidinyl,and pyrazinyl. Exemplary 6-membered heteroaryl groups containing threeor four heteroatoms include, without limitation, triazinyl andtetrazinyl, respectively. Exemplary 7-membered heteroaryl groupscontaining one heteroatom include, without limitation, azepinyl,oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groupsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groupsinclude, without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of representative heteroaryls include the following:

wherein each Y is selected from carbonyl, N, NR⁶⁵, O, and S; and R⁶⁵ isindependently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, and 5-10 membered heteroaryl.

Examples of representative aryl having hetero atoms containingsubstitution include the following:

wherein each W is selected from C(R⁶⁶)₂, NR⁶⁶, O, and S; and each Y isselected from carbonyl, NR⁶⁶, O and S; and R⁶⁶ is independentlyhydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl,C₆-C₁₀ aryl, and 5-10 membered heteroaryl.

“Heteroaralkyl” is a subset of alkyl and heteroaryl, as defined herein,and refers to an optionally substituted alkyl group substituted by anoptionally substituted heteroaryl group.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclyl ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclyl ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is a substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3to 10memberednon-aromatic ring system having ring carbon atoms and 1 to 4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged or spiro ring systemsuch as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containingtwo heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing one heteroatom include,without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8membered heterocyclyl groups containing one heteroatom include, withoutlimitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-memberedheterocyclyl groups fused to a C₆ aryl ring (also referred to herein asa 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

Particular examples of heterocyclyl groups are shown in the followingillustrative examples:

wherein each W is selected from CR⁶⁷, C(R⁶⁷)₂, NR⁶⁷, O, and S; and eachY is selected from NR⁶⁷, O, and S; and R⁶⁷ is independently hydrogen,C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,5-10 membered heteroaryl. These heterocyclyl rings may be optionallysubstituted with one or more substituents selected from the groupconsisting of the group consisting of acyl, acylamino, acyloxy, alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl,sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl,halogen, hydroxy, keto, nitro, thiol, —S-alkyl, S-aryl, —S(O)-alkyl,—S(O)-aryl, —S(O)₂-alkyl, and —S(O)₂-aryl. Substituting groups includecarbonyl or thiocarbonyl which provide, for example, lactam and ureaderivatives.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g.,heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like havingfrom 1 to 5, and particularly from 1 to 3 heteroatoms.

“Acyl” refers to a radical —C(O)R²⁰, where R²⁰ is hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl, asdefined herein. “Alkanoyl” is an acyl group wherein R²⁰ is a group otherthan hydrogen. Representative acyl groups include, but are not limitedto, formyl (—CHO), acetyl (—C(═O)CH₃), cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl (—C(═O)Ph), benzylcarbonyl(—C(═O)CH₂Ph), —C(O)—C₁-C₈ alkyl, —C(O)—(CH₂)_(t)(C₆-C₁₀ aryl),—C(O)—(CH₂)_(t)(5-10 membered heteroaryl), —C(O)—(CH₂)_(t)(C₃-C₁₀cycloalkyl), and —C(O)—(CH₂)_(t)(4-10 membered heterocyclyl), wherein tis an integer from 0 to 4. In certain embodiments, R²¹ is C₁-C₈ alkyl,substituted with halo or hydroxy; or C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, arylalkyl, 5-10 membered heteroaryl orheteroarylalkyl, each of which is substituted with unsubstituted C₁-C₄alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy.

“Acylamino” refers to a radical —NR²²C(O)R²³, where each instance of R²²and R23 is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl as defined herein, or R²² is anamino protecting group. Exemplary “acylamino” groups include, but arenot limited to, formylamino, acetylamino, cyclohexylcarbonylamino,cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino.Particular exemplary “acylamino” groups are —NR²⁴C(O)—C₁-C₈ alkyl,—NR²⁴C(O)—(CH₂)_(t)(C₆-C₁₀ aryl), —NR²⁴C(O)—(CH₂)_(t)(5-10 memberedheteroaryl), —NR²⁴C(O)—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and—NR²⁴C(O)—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integerfrom 0 to 4, and each R²⁴ independently represents H or C₁-C₈ alkyl. Incertain embodiments, R²⁵ is H, C₁-C₈ alkyl, substituted with halo orhydroxy; C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which issubstituted with unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy; and R²⁶ is H, C₁-C₈ alkyl,substituted with halo or hydroxy; C₃-C₁₀cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀aryl, arylalkyl, 5-10 membered heteroaryl orheteroarylalkyl, each of which is substituted with unsubstituted C₁-C₄alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxyl; provided that at least one of R²⁵ and R²⁶ is other than H.

“Acyloxy” refers to a radical —OC(O)R²⁷, where R²⁷ is hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl, as defined herein. Representative examples include, but arenot limited to, formyl, acetyl, cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl. In certainembodiments, R²⁸ is C₁-C₈ alkyl, substituted with halo or hydroxy;C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl, arylalkyl,5-10 membered heteroaryl or heteroarylalkyl, each of which issubstituted with unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy.

“Alkoxy” refers to the group —OR²⁹ where R²⁹ is substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl. Particular alkoxygroups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6carbon atoms. Further particular alkoxy groups have between 1 and 4carbon atoms.

In certain embodiments, R²⁹ is a group that has 1 or more substituents,for instance, from 1 to 5 substituents, and particularly from 1 to 3substituents, in particular 1 substituent, selected from the groupconsisting of amino, substituted amino, C₆-C₁₀ aryl, aryloxy, carboxyl,cyano, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—. Exemplary‘substituted alkoxy’ groups include, but are not limited to,—O—(CH₂)_(t)(C₆-C₁₀ aryl), —O—(CH₂)_(t)(5-10 membered heteroaryl),—O—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and —O—(CH₂)_(t)(4-10 memberedheterocyclyl), wherein t is an integer from 0 to 4 and any aryl,heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves besubstituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy. Particular exemplary‘substituted alkoxy’ groups are —OCF₃, —OCH₂CF₃, —OCH₂Ph,—OCH₂-cyclopropyl, —OCH₂CH₂OH, and —OCH₂CH₂NMe₂.

“Amino” refers to the radical —NH₂.

“Substituted amino” refers to an amino group of the formula —N(R³⁸)₂wherein R³⁸ is hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or an amino protecting group, wherein at leastone of R³⁸ is not a hydrogen. In certain embodiments, each R³⁸ isindependently selected from: hydrogen, C₁-C₈ alkyl, C₃-C₈ alkenyl, C₃-C₈alkynyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl, 4-10 memberedheterocyclyl, or C₃-C₁₀ cycloalkyl; or C₁-C₈ alkyl, substituted withhalo or hydroxy; C₃-C₈ alkenyl, substituted with halo or hydroxy; C₃-C₈alkynyl, substituted with halo or hydroxy, or —(CH₂)_(t)(C₆-C₁₀ aryl),—(CH₂)_(t)(5-10 membered heteroaryl), —(CH₂)_(t)(C₃-C₁₀ cycloalkyl), or—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integer between0 and 8, each of which is substituted by unsubstituted C₁-C₄ alkyl,halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy; or both R³⁸ groups are joined to form an alkylene group.

Exemplary ‘substituted amino’ groups are —NR³⁹—C₁-C₈ alkyl,—NR³⁹—(CH₂)_(t)(C₆-C₁₀ aryl), —NR³⁹—(CH₂)_(t)(5-10 membered heteroaryl),—NR³⁹—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and —NR³⁹—(CH₂)_(t)(4-10 memberedheterocyclyl), wherein t is an integer from 0 to 4, for instance 1 or 2,each R³⁹ independently represents H or C₁-C₈ alkyl, and any alkyl groupspresent, may themselves be substituted by halo, substituted orunsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl,or heterocyclyl groups present, may themselves be substituted byunsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄ alkoxy,unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl, orunsubstituted C₁-C₄ haloalkoxy or hydroxy. For the avoidance of doubtthe term ‘substituted amino’ includes the groups alkylamino, substitutedalkylamino, alkylarylamino, substituted alkylarylamino, arylamino,substituted arylamino, dialkylamino, and substituted dialkylamino asdefined below. Substituted amino encompasses both monosubstituted aminoand disubstituted amino groups.

“Azido” refers to the radical —N₃.

“Carbamoyl” or “amido” refers to the radical —C(O)NH₂.

“Substituted carbamoyl” or “substituted amido” refers to the radical—C(O)N(R⁶²)₂ wherein each R⁶² is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, or an amino protectinggroup, wherein at least one of R⁶² is not a hydrogen. In certainembodiments, R⁶² is selected from H, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl,4-10 membered heterocyclyl, C₆-C₁₀ aryl, aralkyl, 5-10 memberedheteroaryl, and heteroaralkyl; or C₁-C₈ alkyl substituted with halo orhydroxy; or C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which issubstituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy; provided that at least oneR⁶² is other than H.

Exemplary ‘substituted carbamoyl’ groups include, but are not limitedto, —C(O) NR⁶⁴—C₁-C₈ alkyl, —C(O)NR⁶⁴—(CH₂)_(t)(C₆-C₁₀ aryl),—C(O)N⁶⁴—(CH₂)_(t)(5-10 membered heteroaryl), —C(O)NR⁶⁴—(CH₂)_(t)(C₃-C₁₀cycloalkyl), and —C(O)NR⁶⁴—(CH₂)_(t)(4-10 membered heterocyclyl),wherein t is an integer from 0 to 4, each R⁶⁴ independently represents Hor C₁-C₈ alkyl and any aryl, heteroaryl, cycloalkyl or heterocyclylgroups present, may themselves be substituted by unsubstituted C₁-C₄alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy.

‘Carboxy’ refers to the radical —C(O)OH.

“Cyano” refers to the radical —CN.

“Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), andiodo (I). In certain embodiments, the halo group is either fluoro orchloro. In further embodiments, the halo group is iodo.

“Hydroxy” refers to the radical —OH.

“Nitro” refers to the radical —NO₂.

“Cycloalkylalkyl” refers to an alkyl radical in which the alkyl group issubstituted with a cycloalkyl group. Typical cycloalkylalkyl groupsinclude, but are not limited to, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl,cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl,cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.

“Heterocyclylalkyl” refers to an alkyl radical in which the alkyl groupis substituted with a heterocyclyl group. Typical heterocyclylalkylgroups include, but are not limited to, pyrrolidinylmethyl,piperidinylmethyl, piperazinylmethyl, morpholinylmethyl,pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl,and the like.

“Cycloalkenyl” refers to substituted or unsubstituted carbocyclyl grouphaving from 3 to 10 carbon atoms and having a single cyclic ring ormultiple condensed rings, including fused and bridged ring systems andhaving at least one and particularly from 1 to 2 sites of olefinicunsaturation. Such cycloalkenyl groups include, by way of example,single ring structures such as cyclohexenyl, cyclopentenyl,cyclopropenyl, and the like.

“Fused cycloalkenyl” refers to a cycloalkenyl having two of its ringcarbon atoms in common with a second aliphatic or aromatic ring andhaving its olefinic unsaturation located to impart aromaticity to thecycloalkenyl ring.

“Ethenyl” refers to substituted or unsubstituted —(C═C)—.

“Ethylene” refers to substituted or unsubstituted —(C—C)—.

“Ethynyl” refers to —(C≡C)—.

“Nitrogen-containing heterocyclyl” group means a 4- to 7-memberednon-aromatic cyclic group containing at least one nitrogen atom, forexample, but without limitation, morpholine, piperidine (e.g.2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline,imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methyl piperazine. Particular examples includeazetidine, piperidone and piperazone.

“Thioketo” refers to the group ═S.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that results in theformation of a stable compound. The present invention contemplates anyand all such combinations in order to arrive at a stable compound. Forpurposes of this invention, heteroatoms such as nitrogen may havehydrogen substituents and/or any suitable substituent as describedherein which satisfy the valencies of the heteroatoms and results in theformation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂,—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂,—OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂,—P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂,—BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

-   or two geminal hydrogens on a carbon atom are replaced with the    group ═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa),    ═NNR^(bb)C(═O)OR^(aa), ═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or    ═NOR^(cc); each instance of R^(aa) is, independently, selected from    C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀    carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14    membered heteroaryl, or two R^(aa) groups are joined to form a 3-14    membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each    alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and    heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5    R^(dd) groups; each instance of R^(bb) is, independently, selected    from hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),    —C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))OR^(aa),    —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),    —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),    —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,    C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀    carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14    membered heteroaryl, or two R^(bb) groups are joined to form a 3-14    membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each    alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and    heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5    R^(dd) groups; each instance of R^(cc) is, independently, selected    from hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀    alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl,    and 5-14 membered heteroaryl, or two R^(cc) groups are joined to    form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,    wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,    aryl, and heteroaryl is independently substituted with 0, 1, 2, 3,    4, or 5 R^(dd) groups;-   each instance of R^(dd) is, independently, selected from halogen,    —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂,    —N(R^(ff))₂, —N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee),    —SSR^(ee), —C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee),    —OCO₂R^(ee), —C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂,    —NR^(ff)C(═O)R^(ee), —NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂,    —C(═NR^(ff))OR^(ee), —OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee),    —C(═NR^(ff))N(R^(ff))₂, —OC(═NR^(ff))N(R^(ff))₂,    —NR^(ff)C(═NR^(ff))N(R^(ff))₂, —NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂,    —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee), —S(═O)R^(ee), —Si(R^(ee))₃,    —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂, —C(═O)SR^(ee), —C(═S)SR^(ee),    —SC(═S)SR^(ee), —P(═O)₂R^(ee), —P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂,    —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₃₋₁₀ carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl,    5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,    carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently    substituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups, or two geminal    R^(dd) substituents can be joined to form ═O or ═S;-   each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,    C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,    C₆₋₁₀ aryl, 3-10 membered heterocyclyl, and 3-10 membered    heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,    heterocyclyl, aryl, and heteroaryl is independently substituted with    0, 1, 2, 3, 4, or 5 R^(gg) groups;-   each instance of R^(ff) is, independently, selected from hydrogen,    C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀    carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10    membered heteroaryl, or two R^(ff) groups are joined to form a 3-14    membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each    alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and    heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5    R^(gg) groups; and-   each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,    —SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,    —N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃    ⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,    —SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆    alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂,    —C(═O)N(C₁₋₆ alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl),    —N(C₁₋₆ alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆    alkyl)₂, —NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl),    —OC(═NH)(C₁₋₆ alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂,    —C(═NH)NH(C₁₋₆ alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂,    —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂,    —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl), —SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆    alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl,    —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆ alkyl)₃—C(═S)N(C₁₋₆    alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆ alkyl),    —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆ alkyl),    —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆ alkyl)₂,    C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀    carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 membered    heteroaryl; or two geminal R^(gg) substituents can be joined to form    ═O or ═S; wherein X⁻ is a counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, sulfonate ions(e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonicacid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate,ethanoate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, and the like).

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quarternary nitrogenatoms. Exemplary nitrogen atom substitutents include, but are notlimited to, hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to a nitrogen atom are joinedto form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined above.

In certain embodiments, the substituent present on a nitrogen atom is anitrogen protecting group (also referred to as an amino protectinggroup). Nitrogen protecting groups include, but are not limited to, —OH,—N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa),—C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂,—SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂,—C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl (e.g., aralkyl,heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl groups,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2,3, 4, or 5 R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd)are as defined herein. Nitrogen protecting groups are well known in theart and include those described in detail in Protecting Groups inOrganic Synthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, JohnWiley & Sons, 1999, incorporated herein by reference.

For example, nitrogen protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g.,—C(═O)OR^(aa)) include, but are not limited to, methyl carbamate, ethylcarbamante, 9-fluorenylmethyl carbamate (Fmoc),9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethylcarbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate(Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate(Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc),2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloropacyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g.,—S(═O)₂R^(aa)) include, but are not limited to, p-toluenesulfonamide(Ts), benzenesulfonamide, 2,3,6,trimethyl-4-methoxybenzenesulfonamide(Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl (10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N-(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-pnitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,onitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to as a hydroxyl protectinggroup). Oxygen protecting groups include, but are not limited to,—R^(aa), N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃,—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and—P(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein. Oxygen protecting groups are well known in the art and includethose described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyllmethoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyllbenzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, pchlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate(TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec),2-(triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate,alkyl vinyl carbonate alkyl allyl carbonate, alkyl pnitrophenylcarbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate,alkyl 3,4-dimethoxybenzyl carbonate, alkyl onitrobenzyl carbonate, alkylp-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate,4-ethoxylnapththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts).

In certain embodiments, the substituent present on an sulfur atom is ansulfur protecting group (also referred to as a thiol protecting group).Sulfur protecting groups include, but are not limited to, —R^(aa),—N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃,—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and—P(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein. Sulfur protecting groups are well known in the art and includethose described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference.

“Compounds of the present invention”, and equivalent expressions, aremeant to embrace the compounds as hereinbefore described, in particularcompounds according to any of the Formula herein recited and/ordescribed, which expression includes the prodrugs, the pharmaceuticallyacceptable salts, and the solvates, e.g., hydrates, where the context sopermits. Similarly, reference to intermediates, whether or not theythemselves are claimed, is meant to embrace their salts, and solvates,where the context so permits.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

Other Definitions

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or a state government or thecorresponding agency in countries other than the United States, or thatis listed in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals, and more particularly, in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. In particular,such salts are non-toxic may be inorganic or organic acid addition saltsand base addition salts. Specifically, such salts include: (1) acidaddition salts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non-toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like. The term“pharmaceutically acceptable cation” refers to an acceptable cationiccounter-ion of an acidic functional group. Such cations are exemplifiedby sodium, potassium, calcium, magnesium, ammonium, tetraalkylammoniumcations, and the like (see, e.g., Berge, et al., J. Pharm. Sci. 66(1):1-79 (January '77).

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a compound of the invention isadministered.

“Pharmaceutically acceptable metabolically cleavable group” refers to agroup which is cleaved in vivo to yield the parent molecule of thestructural Formula indicated herein. Examples of metabolically cleavablegroups include —COR, —COOR,—CONRR and —CH₂OR radicals, where R isselected independently at each occurrence from alkyl, trialkylsilyl,carbocyclic aryl or carbocyclic aryl substituted with one or more ofalkyl, halogen, hydroxy or alkoxy. Specific examples of representativemetabolically cleavable groups include acetyl, methoxycarbonyl, benzoyl,methoxymethyl and trimethylsilyl groups.

“Prodrugs” refers to compounds, including derivatives of the compoundsof the invention,which have cleavable groups and become by solvolysis orunder physiological conditions the compounds of the invention that arepharmaceutically active in vivo. Such examples include, but are notlimited to, choline ester derivatives and the like, N-alkylmorpholineesters and the like. Other derivatives of the compounds of thisinvention have activity in both their acid and acid derivative forms,but in the acid sensitive form often offers advantages of solubility,tissue compatibility, or delayed release in the mammalian organism (see,Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam1985). Prodrugs include acid derivatives well know to practitioners ofthe art, such as, for example, esters prepared by reaction of the parentacid with a suitable alcohol, or amides prepared by reaction of theparent acid compound with a substituted or unsubstituted amine, or acidanhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters,amides and anhydrides derived from acidic groups pendant on thecompounds of this invention are particular prodrugs. In some cases it isdesirable to prepare double ester type prodrugs such as (acyloxy)alkylesters or ((alkoxycarbonyl)oxy)alkylesters. Particularly the C₁ to C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, C₇-C₁₂ substituted aryl, andC₇-C₁₂ arylalkyl esters of the compounds of the invention.

“Solvate” refers to forms of the compound that are associated with asolvent or water (also referred to as “hydrate”), usually by asolvolysis reaction. This physical association includes hydrogenbonding. Conventional solvents include water, ethanol, acetic acid andthe like. The compounds of the invention may be prepared e.g. incrystalline form and may be solvated or hydrated. Suitable solvatesinclude pharmaceutically acceptable solvates, such as hydrates, andfurther include both stoichiometric solvates and non-stoichiometricsolvates. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Representative solvates includehydrates, ethanolates and methanolates.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g., infant, child, adolescent) or adult subject(e.g., young adult, middleaged adult or senior adult)) and/or anon-human animal, e.g., a mammal such as primates (e.g., cynomolgusmonkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents,cats, and/or dogs. In certain embodiments, the subject is a human. Incertain embodiments, the subject is a non-human animal. The terms“human”, “patient” and “subject” are used interchangeably herein.

“Therapeutically effective amount” means the amount of a compound that,when administered to a subject for treating a disease, is sufficient toeffect such treatment for the disease. The “therapeutically effectiveamount” can vary depending on the compound, the disease and itsseverity, and the age, weight, etc., of the subject to be treated.

“Preventing” or “prevention” refers to a reduction in risk of acquiringor developing a disease or disorder (i.e., causing at least one of theclinical symptoms of the disease not to develop in a subject not yetexposed to a disease-causing agent, or predisposed to the disease inadvance of disease onset.

The term “prophylaxis” is related to “prevention”, and refers to ameasure or procedure the purpose of which is to prevent, rather than totreat or cure a disease. Non-limiting examples of prophylactic measuresmay include the administration of vaccines; the administration of lowmolecular weight heparin to hospital patients at risk for thrombosisdue, for example, to immobilization; and the administration of ananti-malarial agent such as chloroquine, in advance of a visit to ageographical region where malaria is endemic or the risk of contractingmalaria is high.

“Treating” or “treatment” of any disease or disorder refers, in certainembodiments, to ameliorating the disease or disorder (i.e., arrestingthe disease or reducing the manifestation, extent or severity of atleast one of the clinical symptoms thereof). In another embodiment“treating” or “treatment” refers to ameliorating at least one physicalparameter, which may not be discernible by the subject. In yet anotherembodiment, “treating” or “treatment” refers to modulating the diseaseor disorder, either physically, (e.g., stabilization of a discerniblesymptom), physiologically, (e.g., stabilization of a physicalparameter), or both. In a further embodiment, “treating” or “treatment”relates to slowing the progression of the disease.

As used herein, the term “isotopic variant” refers to a compound thatcontains unnatural proportions of isotopes at one or more of the atomsthat constitute such compound. For example, an “isotopic variant” of acompound can contain one or more non-radioactive isotopes, such as forexample, deuterium (²H or D), carbon-13 (¹³C), nitrogen-15 (¹⁵N), or thelike. It will be understood that, in a compound where such isotopicsubstitution is made, the following atoms, where present, may vary, sothat for example, any hydrogen may be ²H/D, any carbon may be ¹³C, orany nitrogen may be ¹⁵N, and that the presence and placement of suchatoms may be determined within the skill of the art. Likewise, theinvention may include the preparation of isotopic variants withradioisotopes, in the instance for example, where the resultingcompounds may be used for drug and/or substrate tissue distributionstudies. The radioactive isotopes tritium, i.e., ³H, and carbon-14,i.e., ¹⁴C, are particularly useful for this purpose in view of theirease of incorporation and ready means of detection. Further, compoundsmay be prepared that are substituted with positron emitting isotopes,such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, and would be useful in Positron EmissionTopography (PET) studies for examining substrate receptor occupancy. Allisotopic variants of the compounds provided herein, radioactive or not,are intended to be encompassed within the scope of the invention.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, when it is bonded to four different groups, a pairof enantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR— and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of it electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenylnitromethane, which arelikewise formed by treatment with acid or base. Tautomeric forms may berelevant to the attainment of the optimal chemical reactivity andbiological activity of a compound of interest.

As used herein a pure enantiomeric compound is substantially free fromother enantiomers or stereoisomers of the compound (i.e., inenantiomeric excess). In other words, an “S” form of the compound issubstantially free from the “R” form of the compound and is, thus, inenantiomeric excess of the “R” form. The term “enantiomerically pure” or“pure enantiomer” denotes that the compound comprises more than 75% byweight, more than 80% by weight, more than 85% by weight, more than 90%by weight, more than 91% by weight, more than 92% by weight, more than93% by weight, more than 94% by weight, more than 95% by weight, morethan 96% by weight, more than 97% by weight, more than 98% by weight,more than 98.5% by weight, more than 99% by weight, more than 99.2% byweight, more than 99.5% by weight, more than 99.6% by weight, more than99.7% by weight, more than 99.8% by weight or more than 99.9% by weight,of the enantiomer. In certain embodiments, the weights are based upontotal weight of all enantiomers or stereoisomers of the compound.

As used herein and unless otherwise indicated, the term“enantiomerically pure R-compound” refers to at least about 80% byweight R-compound and at most about 20% by weight S-compound, at leastabout 90% by weight R-compound and at most about 10% by weightS-compound, at least about 95% by weight R-compound and at most about 5%by weight S-compound, at least about 99% by weight R-compound and atmost about 1% by weight S-compound, at least about 99.9% by weightR-compound or at most about 0.1% by weight S-compound. In certainembodiments, the weights are based upon total weight of compound.

As used herein and unless otherwise indicated, the term“enantiomerically pure 5-compound” or “S-compound” refers to at leastabout 80% by weight S-compound and at most about 20% by weightR-compound, at least about 90% by weight S-compound and at most about10% by weight R-compound, at least about 95% by weight S-compound and atmost about 5% by weight R-compound, at least about 99% by weightS-compound and at most about 1% by weight R-compound or at least about99.9% by weight S-compound and at most about 0.1% by weight R-compound.In certain embodiments, the weights are based upon total weight ofcompound.

In the compositions provided herein, an enantiomerically pure compoundor a pharmaceutically acceptable salt, solvate, hydrate or prodrugthereof can be present with other active or inactive ingredients. Forexample, a pharmaceutical composition comprising enantiomerically pureR-compound can comprise, for example, about 90% excipient and about 10%enantiomerically pure R-compound. In certain embodiments, theenantiomerically pure R-compound in such compositions can, for example,comprise, at least about 95% by weight R-compound and at most about 5%by weight S-compound, by total weight of the compound. For example, apharmaceutical composition comprising enantiomerically pure S-compoundcan comprise, for example, about 90% excipient and about 10%enantiomerically pure S-compound. In certain embodiments, theenantiomerically pure S-compound in such compositions can, for example,comprise, at least about 95% by weight S-compound and at most about 5%by weight R-compound, by total weight of the compound. In certainembodiments, the active ingredient can be formulated with little or noexcipient or carrier.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof.

Unless indicated otherwise, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof. Themethods for the determination of stereochemistry and the separation ofstereoisomers are well-known in the art.

One having ordinary skill in the art of organic synthesis will recognizethat the maximum number of heteroatoms in a stable, chemically feasibleheterocyclic ring, whether it is aromatic or non-aromatic, is determinedby the size of the ring, the degree of unsaturation and the valence ofthe heteroatoms. In general, a heterocyclic ring may have one to fourheteroatoms so long as the heteroaromatic ring is chemically feasibleand stable.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In certain aspects, provided herein are pyridylmethylamine compoundsanti-Aβ production, aggregation, inhibition of oxidative stress, andmodulation of amyloid precursor protein (APP) translation properties,and pharmaceutical compositions thereof. Also provided are methods forpreventing and/or treating medical conditions in mammals, such asneurodegenerative diseases including Alzheimer's, using the compoundsand pharmaceutical compositions provided herein.

In certain aspects, provided herein are pyridylmethylamine compoundsuseful for preventing and/or treating a broad range of neurodegenerativeconditions, such as AD, Down's syndrome, Parkinson's disease and others.

In another aspect, provided here are methods for preventing, treating orameliorating in a mammal various medical conditions, such asneurodegenerative conditions, which comprises administering to themammal an effective medical condition treating amount of apyridylmethylamine compound.

In one specific aspect, provided herein are method for preventing,treating or ameliorating in a mammal a medical condition, such asneurodegenerative conditions, which comprises administering to themammal an effective medical condition treating amount of a compoundaccording to formula I:

or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or acombination thereof;

-   wherein:    -   R₃, R₄, R₅ and R₆ are independently selected from the group        consisting of hydrogen, halogen, substituted or unsubstituted        C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,        substituted or unsubstituted C₂₋₈ alkynyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted heterocyclyl, halogen,        trihalomethyl, —CN, —NO₂, —NH₂, —OR₁, —NR₁R₂, —S(O)₀₋₂R₁,        —SO₂NR₁R₂, —CO₂R₁, —C(O)NR₁R₂, —N(R₁)SO₂R₂, —C(O)R₁,        —N(R₁)C(O)R₂, —N(R₁)CO₂R₂, —OC(O)NR₁R₂, —OC(O)R₁, and optionally        substituted lower alkyl;    -   R₁ and R₂ are independently selected from the group consisting        of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,        substituted or unsubstituted C₂₋₈ alkenyl, substituted or        unsubstituted C₂₋₈ alkynyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, substituted or        unsubstituted heterocyclyl, and optionally substituted lower        alkyl;    -   R is selected from the group consisting of hydrogen, substituted        or unsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈        alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, substituted        or unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted heterocyclyl, —S(O)₀₋₂R₁,        —SO₂NR₁R₂, —CO₂R₁, —C(O)NR₁R₂, —N(R₁)SO₂R₂, —N(R₁)C(O)R₂,        —N(R₁)CO₂R₂, —C(O)R₁, and optionally substituted lower alkyl;    -   R′ is selected from the group having formula II:

-   -   wherein    -   the subscript m is 1, 2, 3, or 4; the subscript n is 0, 1, 2, or        3;    -   R″ is selected from the group consisting of hydrogen, halogen,        substituted or unsubstituted C₁₋₈ alkyl, substituted or        unsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈        alkynyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heterocyclyl, halogen, trihalomethyl, —CN, —NO₂, —NH₂, —OR₁,        —NR₁R₂, —S(O)₀₋₂R₁, —SO₂NR₁R₂, —CO₂R₁, —C(O)NR₁R₂, —N(R₁)SO₂R₂,        —C(O)R₁, —N(R₁)C(O)R₂, —N(R₁)CO₂R₂, OC(O)NR₁R₂, —OC(O)R₁, and        optionally substituted lower alkyl;    -   R″ is H or substituted or unsubstituted C₁₋₈ alkyl or        substituted or unsubstituted C₂₋₈ alkenyl, substituted or        unsubstituted C₂₋₈ alkynyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, substituted or        unsubstituted heterocyclyl, trihalomethyl, or selected from the        group having formula III:

-   -   wherein    -   R_(a) is selected from the group consisting of hydrogen,        halogen, substituted or unsubstituted C₁₋₈ alkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl

In one embodiment, with respect to the method, the medical condition isAD.

In one embodiment, the medical condition is Down's syndrome.

In one embodiment, the medical condition is Parkinson's disease.

In one embodiment, with respect to the method, the medical condition isassociated with modulation of Aβ production.

In one embodiment, with respect to the method, the medical condition isassociated with inhibition of Aβ production.

In one embodiment, with respect to the method, the medical condition isassociated with modulation of APP expression or APP translation.

In another specific aspect, provided herein are pharmaceuticalcompositions for preventing, treating or ameliorating in a mammal amedical condition, such as neurodegenerative conditions, which comprisesa compound according to formula I:

or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or acombination thereof;

wherein R, R′, R₃, R₄, R₅, and R₆ are as described above.

In one embodiment, with respect to the method or the pharmaceuticalcomposition the compound is according to formula IVa or IVb:

or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or acombination thereof;

-   and wherein R, R_(a), R″, R′″, R₃, R₄, R₅, R₆, m or n are as    described for formula I.

In one embodiment, with respect to the formula IVa-IVb, the subscript nis 0 or 1.

In one embodiment, with respect to the formula I, IVa-IVb, R is H.

In one embodiment, with respect to the formula I, IVa-IVb, R″ is H.

In one embodiment, with respect to the formula I, IVa-IVb, R′″ is H.

In one embodiment, with respect to the formula I, IVa-IVb, R_(a) is H.

In one embodiment, with respect to the formula I, IVa-IVb, R_(a) is Me.

In one embodiment, with respect to the formula I, IVa-IVb, R₃ is H.

In one embodiment, with respect to the formula I, IVa-IVb, R₄ is H.

In one embodiment, with respect to the formula I, IVa-IVb, R₅ is H.

In one embodiment, with respect to the formula I, IVa-IVb, R₆ is H.

In one particular embodiment, with respect to the method or thepharmaceutical composition the compound is according to formula V:

or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or acombination thereof.

In one embodiment, with respect to the method or the pharmaceuticalcomposition, the compound is a pharmaceutically acceptable salt.

In one embodiment, with respect to the method or the pharmaceuticalcomposition, the compound is an acid salt.

In another specific aspect, provided herein are pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and apharmaceutically effective amount of a compound of formula I, IVa-IVb,or V.

In one embodiment, with respect to the pharmaceutical composition thecarrier is a parenteral carrier, oral or topical carrier.

In another specific aspect, provided herein are methods for preventing,treating or ameliorating in a mammal a medical condition, whichcomprises administering to the mammal an effective medical conditiontreating amount of a compound according to formula V:

or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or acombination thereof.

In one embodiment, with respect to the method, the medical condition isAlzeimer's disease.

In one embodiment, the medical condition is Down's syndrome.

In one embodiment, the medical condition is Parkinson's disease.

In one embodiment, with respect to the method, the medical condition isassociated with modulation of Aβ production.

In one embodiment, with respect to the method, the medical condition isassociated with inhibition of Aβ production.

In one embodiment, with respect to the method, the medical condition isassociated with modulation of APP expression or APP translation.

In another specific aspect, provided herein are methods for lowering theload of Aβ plaque, which comprises administering to the mammal aneffective treating amount of a compound according to formula I, IVa,IVb, or V.

In another specific aspect, provided herein are methods for lowering thebrain Aβ level, which comprises administering to the mammal an effectivetreating amount of a compound according to formula I, IVa, IVb, or V.

In one embodiment, with respect to the method, the compound is apharmaceutically acceptable salt, solvate, hydrate, prodrug,stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or acombination thereof of a compound according to any one of formuladescribed herein.

In one particular embodiment, with respect to the compounds of formulaI, IVa-IVb, or V, the compound is a pharmaceutically acceptable salt. Inone particular embodiment, the salt is a quaternary salt.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and apharmaceutically effective amount of a compound of compound of formulaI, IVa-IVb, or V.

In one particular embodiment, with respect to the pharmaceuticalformulation, the carrier is a parenteral carrier, oral or topicalcarrier.

In yet another aspect, the present invention provides a method forpreventing, treating, ameliorating or managing a disease or conditionwhich comprises administering to a patient in need of such prevention,treatment, amelioration or management, a prophylactically ortherapeutically effective amount of a compound or pharmaceuticalcomposition of compound of formula I, IVa-IVb, or V.

In one embodiment, the disease or condition is a neurological condition.In one embodiment, the disease or condition is neurodegeneration. In oneembodiment, the disease or condition is AD.

In yet another aspect, the present invention provides a compound orpharmaceutical composition of compound of formula I, IVa-IVb, or V; or apharmaceutically acceptable salt or solvate thereof for use as apharmaceutical or a medicament.

In yet another aspect, the present invention provides a use of acompound of formula I, IVa-IVb, or V, or a pharmaceutically acceptablesalt, solvate or composition thereof, for the manufacture of amedicament to treat a disease or condition associated with AD.

The present invention also relates to the pharmaceutically acceptableacid addition salts of compounds of formula I. The acids which are usedto prepare the pharmaceutically acceptable salts are those which formnon-toxic acid addition salts, i.e. slats containing pharmacologicallyacceptable anions such as the hydrochloride, hydroiodide, hydrobromide,nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate,tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonateand the like.

In another aspect, the present invention provides pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and apharmaceutically effective amount of a compound of formula I. In oneembodiment, the carrier is a parenteral carrier, oral or topicalcarrier.

In yet another aspect, the present invention provides a method forpreventing, treating, ameliorating or managing a disease or conditionwhich comprises administering to a patient in need of such prevention,treatment, amelioration or management, a prophylactically ortherapeutically effective amount of a compound of formula I, IVa-IVb, orV, or the pharmaceutical composition thereof.

In yet another aspect, the present invention provides a compound offormula I, IVa-IVb, or V or a pharmaceutically acceptable salt orsolvate thereof for use as a pharmaceutical or a medicament.

In yet another aspect, the present invention provides a use of acompound of formula I, IVa-IVb, or V, or a pharmaceutically acceptablesalt, solvate or composition thereof, for the manufacture of amedicament to treat a disease or condition associated with AD in mammal.

In yet another aspect, the present invention provides a method oftreatment of a mammal, including a human being, to treat a disease forwhich a AD is indicated, including treating said mammal with aneffective amount of a compound of formula I, IVa-IVb, or V, or with apharmaceutically acceptable salt, solvate or composition thereof.

In yet another aspect, the present invention provides a combination of acompound of formula I, IVa-IVb, or V, and another pharmacologicallyactive agent.

Additional embodiments within the scope provided herein are set forth innon-limiting fashion elsewhere herein and in the examples. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting in any manner.

Pharmaceutical Compositions

In another aspect, the invention provides a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a pharmaceuticallyeffective amount of a compound of Formula I.

When employed as pharmaceuticals, the compounds provided herein aretypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared in a manner well known in thepharmaceutical art and comprise at least one active compound.

In certain embodiments, with respect to the pharmaceutical composition,the carrier is a parenteral carrier, oral or topical carrier.

The present invention also relates to a compound or pharmaceuticalcomposition of compound according to Formula I; or a pharmaceuticallyacceptable salt or solvate thereof for use as a pharmaceutical or amedicament.

Generally, the compounds provided herein are administered in atherapeutically effective amount. The amount of the compound actuallyadministered will typically be determined by a physician, in the lightof the relevant circumstances, including the condition to be treated,the chosen route of administration, the actual compound administered,the age, weight, and response of the individual patient, the severity ofthe patient's symptoms, and the like.

The pharmaceutical compositions provided herein can be administered by avariety of routes including oral, rectal, transdermal, subcutaneous,intravenous, intramuscular, and intranasal. Depending on the intendedroute of delivery, the compounds provided herein are preferablyformulated as either injectable or oral compositions or as salves, aslotions or as patches all for transdermal administration.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. In such compositions, the compound is usually aminor component (from about 0.1 to about 50% by weight or preferablyfrom about 1 to about 40% by weight) with the remainder being variousvehicles or carriers and processing aids helpful for forming the desireddosing form.

Liquid forms suitable for oral administration may include a suitableaqueous or non-aqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable carrier and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s), generally in an amountranging from about 0.01 to about 20% by weight, preferably from about0.1 to about 20% by weight, preferably from about 0.1 to about 10% byweight, and more preferably from about 0.5 to about 15% by weight. Whenformulated as a ointment, the active ingredients will typically becombined with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream with,for example an oil-in-water cream base. Such transdermal formulationsare well-known in the art and generally include additional ingredientsto enhance the dermal penetration of stability of the active ingredientsor the formulation. All such known transdermal formulations andingredients are included within the scope provided herein.

The compounds provided herein can also be administered by a transdermaldevice. Accordingly, transdermal administration can be accomplishedusing a patch either of the reservoir or porous membrane type, or of asolid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

The above-described components for orally administrable, injectable, ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's The Science and Practice of Pharmacy, 21stedition, 2005, Publisher: Lippincott Williams & Wilkins, which isincorporated herein by reference.

The compounds of this invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

The present invention also relates to the pharmaceutically acceptableformulations of compounds of Formula I. In certain embodiments, theformulation comprises water. In another embodiment, the formulationcomprises a cyclodextrin derivative. In certain embodiments, theformulation comprises hexapropyl-β-cyclodextrin. In a more particularembodiment, the formulation comprises hexapropyl-β-cyclodextrin (10-50%in water).

The present invention also relates to the pharmaceutically acceptableacid addition salts of compounds of Formula I. The acids which are usedto prepare the pharmaceutically acceptable salts are those which formnon-toxic acid addition salts, i.e. salts containing pharmacologicallyacceptable aniovs such as the hydrochloride, hydroiodide, hydrobromide,nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate,tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate,and the like.

The following formulation examples illustrate representativepharmaceutical compositions that may be prepared in accordance with thisinvention. The present invention, however, is not limited to thefollowing pharmaceutical compositions.

Formulation 1—Tablets

A compound of the invention may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into240-270 mg tablets (80-90 mg of active compound per tablet) in a tabletpress.

Formulation 2—Capsules

A compound of the invention may be admixed as a dry powder with a starchdiluent in an approximate 1:1 weight ratio. The mixture is filled into250 mg capsules (125 mg of active compound per capsule).

Formulation 3—Liquid

A compound of the invention (125 mg) may be admixed with sucrose (1.75g) and xanthan gum (4 mg) and the resultant mixture may be blended,passed through a No. 10 mesh U.S. sieve, and then mixed with apreviously made solution of microcrystalline cellulose and sodiumcarboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10mg), flavor, and color are diluted with water and added with stirring.Sufficient water may then be added to produce a total volume of 5 mL.

Formulation 4—Tablets

A compound of the invention may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into450-900 mg tablets (150-300 mg of active compound) in a tablet press.

Formulation 5—Injection

A compound of the invention may be dissolved or suspended in a bufferedsterile saline injectable aqueous medium to a concentration ofapproximately 5 mg/mL.

Formulation 6—Tablets

A compound of the invention may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into10-500 mg tablets (1-250 mg of active compound per tablet) in a tabletpress.

Formulation 7—Tablets

A compound of the invention may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into30-90 mg tablets (10-30 mg of active compound per tablet) in a tabletpress.

Formulation 8—Tablets

A compound of the invention may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into0.3-30 mg tablets (0.1-10 mg of active compound per tablet) in a tabletpress.

Formulation 9—Tablets

A compound of the invention may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into150-240 mg tablets (50-80 mg of active compound per tablet) in a tabletpress.

Formulation 10—Tablets

A compound of the invention may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into10-500 mg tablets (1-250 mg of active compound per tablet) in a tabletpress.

Methods of Treatment

Alzheimer's disease (AD) causes dementia in 5.4 million patients in theUSA. AD is a result of chronic and vast accumulation of a toxic andhydrophobic β-amyloid peptide (Aβ) peptide in the brain that drivessynaptopathy, triggers the occurrence of neurofibrillary pathology andneuroinflammation, and associated neuronal loss. Early-onset, familialAD cases are linked to APP, presenilin (PS)1 or PS2 mutations, whicheither increase total Aβ production, or favor secretion of more toxicand aggregation prone Aβ42 at the expense of more soluble Aβ40. Reasonsfor Aβ accumulation in the more prevalent sporadic AD are lessconspicuous, but likely are a combination of inherited features (e.g.apolipoprotein E isoform status) and acquired factors resulting in anage-progressing mismatch between production and clearance of Aβ.

Accumulation of Aβ is driven by its inherently low solubility andnatural propensity to self-aggregate into toxic oligomers and insolublefibrils. Aβ oligomers are particularly toxic to excitatory synapses onhippocampal neurons, while Aβ plaques are associated with deleteriousactivation of microglia and dystrophy of neurites. Furthermore, selfaggregation of Aβ affects its clearance, which in turn furtherperpetuates brain Aβ accumulation. Aβ accumulation and resultingneurodegenerative cascade can predate by many years the prodromalamnestic symptoms seen in patients with mild cognitive impairment (MCI).

Development of therapies targeting the build up and toxicity of Aβ havebeen advocated as means of primary prevention (preclinical→MCI),secondary AD prevention (MCI→AD), and as a potential therapy appliedduring early stages of the disease when Aβ toxicity still plays asignificant role, actively influencing progression of neurodegeneration.Among the pharmacological targets being pursued are drugs to reduce Aβproduction (notably APP secretase inhibitors), to prevent Aβaggregation, to reduce Aβ plaques (active immunization), and to promoteAβ clearance via passive immunotherapy or targeting BBB receptors forAβ. Several compounds have been registered through IND process andtested in clinical trials, but thus far, no effective disease modifyingagent for AD has received FDA approval. Failure of AD clinical trialsthus far has been attributed to lack of adequate efficacy of testedcompound in humans or their toxicity. For example, a γ secretaseinhibitor Semagacestat (LY450139), showed a direct effect on Aβproduction in human volunteers, but in the interim analysis of Phase IIIclinical trial was found to be associated with worsening of cognitivemeasures in AD patients and increased malignancy risk, likely due itsoff target effect on Notch-1 signaling pathway. Passive immunizationappears to be the most clinically advanced and promising therapeuticapproach for AD. Bapinezumab or intravenous immunoglobulins may beseeking FDA approval within the next few years. However, these drugsrequire constant and repetitive infusions, which would be a nuisance tothe patients and increase cost of care. Given chronicity of ADpathogenesis, treatments targeting the Aβ cascade would likely need tobe administered on a long-term basis. A need for well-tolerated,effective, orally administered anti-Aβ compounds remains unmet. Severalsecond generation, orally available inhibitors of β and γ secretases arein development. However, it would still be necessary to demonstratesatisfactory effect in humans, without producing significant off targeteffects.

Aβ is a product of enzymatic cleavage of the amyloid precursor protein(APP) by βand γ secretases. Aβ production can be ameliorated bymodulation of APP expression. Modulation of APP expression is unlikelyto evoke off target effects of APP secretase inhibitors. Also it isunlikely to be associated with vasogenic complications of anti-Aβpassive immunization. While development of APP secretases inhibitors andanti-Aβ immunization approaches are widely pursued, very few moleculescapable of modulating APP expression and showing drug developmentpotential have been identified thus far. Furthermore, studies in AD Tgmice has indicated that modulation of APP expression and passiveimmunization can provide additive benefits on lowering Aβ load.Therefore, APP expression modulators constitute an underdeveloped, butpromising approach for mono and combined AD therapy and prevention. Thisapplication proposes development of a novel class of APP modulators.

The compounds of the present invention are used as therapeutic agentsfor the treatment of conditions in mammals. In one particular aspect,these compounds can be used for the treatment of disease or conditionrelated to neurological conditions. Specifically these compounds can beused for the treatment of disease or condition related to AD.

Accordingly, the compounds and pharmaceutical compositions providedherein find use as therapeutics for preventing and/or treatingconditions including but not limited to AD, Parkinson's disease, Down'ssyndrome and others in mammals including humans and non-human mammals.Thus, and as stated earlier, the present invention includes within itsscope, and extends to, the recited methods of treatment, as well as tothe compounds for such methods, and to the use of such compounds for thepreparation of medicaments useful for such methods.

In a method of treatment aspect, provided herein is a method of treatinga mammal susceptible to or afflicted with a condition associated withAD, which method comprises administering an effective amount of one ormore of the pharmaceutical compositions just described.

In yet another method of treatment aspect, provided herein is a methodof treating a subject susceptible to or afflicted with AD.

As a further aspect there is provided the present compounds for use as apharmaceutical especially in the treatment or prevention of theaforementioned conditions and diseases. We also provide the use of thepresent compounds in the manufacture of a medicament for the treatmentor prevention of one of the aforementioned conditions and diseases.

When used to prevent the onset of a neurological condition, thecompounds provided herein will be administered to a patient at risk fordeveloping the condition, typically on the advice and under thesupervision of a physician, at the dosage levels described above.Patients at risk for developing a particular condition generally includethose that have a family history of the condition, or those who havebeen identified by genetic testing or screening to be particularlysusceptible to developing the condition.

The compounds provided herein can be administered as the sole activeagent or they can be administered in combination with other agents,including other active amines and derivatives. Administration incombination can proceed by any technique apparent to those of skill inthe art including, for example, separate, sequential, concurrent andalternating administration.

General Synthetic Procedures

The compounds provided herein can be purchased or prepared from readilyavailable starting materials using the following general methods andprocedures. See, e.g., Synthetic Schemes below. It will be appreciatedthat where typical or preferred process conditions (i.e., reactiontemperatures, times, mole ratios of reactants, solvents, pressures,etc.) are given, other process conditions can also be used unlessotherwise stated. Optimum reaction conditions may vary with theparticular reactants or solvent used, but such conditions can bedetermined by one skilled in the art by routine optimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and P. G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, New York, 1991, andreferences cited therein.

The compounds provided herein may be isolated and purified by knownstandard procedures. Such procedures include (but are not limited to)recrystallization, column chromatography or HPLC. The following schemesare presented with details as to the preparation of representativesubstituted biarylamides that have been listed herein. The compoundsprovided herein may be prepared from known or commercially availablestarting materials and reagents by one skilled in the art of organicsynthesis.

The enantiomerically pure compounds provided herein may be preparedaccording to any techniques known to those of skill in the art. Forinstance, they may be prepared by chiral or asymmetric synthesis from asuitable optically pure precursor or obtained from a racemate by anyconventional technique, for example, by chromatographic resolution usinga chiral column, TLC or by the preparation of diastereoisomers,separation thereof and regeneration of the desired enantiomer. See,e.g., “Enantiomers, Racemates and Resolutions,” by J. Jacques, A.Collet, and S. H. Wilen, (Wiley-Interscience, New York, 1981); S. H.Wilen, A. Collet, and J. Jacques, Tetrahedron, 2725 (1977); E. L. ElielStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and S. H.Wilen Tables of Resolving Agents and Optical Resolutions 268 (E. L.Eliel ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972,Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H. Wilenand Lewis N. Manda (1994 John Wiley & Sons, Inc.), and StereoselectiveSynthesis A Practical Approach, Mihály Nógrádi (1995 VCH Publishers,Inc., NY, N.Y.).

In certain embodiments, an enantiomerically pure compound of formula (1)may be obtained by reaction of the racemate with a suitable opticallyactive acid or base. Suitable acids or bases include those described inBighley et al., 1995, Salt Forms of Drugs and Adsorption, inEncyclopedia of Pharmaceutical Technology, vol. 13, Swarbrick & Boylan,eds., Marcel Dekker, New York; ten Hoeve & H. Wynberg, 1985, Journal ofOrganic Chemistry 50:4508-4514; Dale & Mosher, 1973, J. Am. Chem. Soc.95:512; and CRC Handbook of Optical Resolution via Diastereomeric SaltFormation, the contents of which are hereby incorporated by reference intheir entireties.

Enantiomerically pure compounds can also be recovered either from thecrystallized diastereomer or from the mother liquor, depending on thesolubility properties of the particular acid resolving agent employedand the particular acid enantiomer used. The identity and optical purityof the particular compound so recovered can be determined by polarimetryor other analytical methods known in the art. The diasteroisomers canthen be separated, for example, by chromatography or fractionalcrystallization, and the desired enantiomer regenerated by treatmentwith an appropriate base or acid. The other enantiomer may be obtainedfrom the racemate in a similar manner or worked up from the liquors ofthe first separation.

In certain embodiments, enantiomerically pure compound can be separatedfrom racemic compound by chiral chromatography. Various chiral columnsand eluents for use in the separation of the enantiomers are availableand suitable conditions for the separation can be empirically determinedby methods known to one of skill in the art. Exemplary chiral columnsavailable for use in the separation of the enantiomers provided hereininclude, but are not limited to CHIRALCEL® OB, CHIRALCEL® OB-H,CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL®OJ and CHIRALCEL® OK.

General processes for preparing compounds of formula (I) are provided asfurther embodiments of the invention and are illustrated in Scheme 1.

Synthesis of Representative Compounds

The syntheses of representative compounds of this invention can becarried out in accordance with the method set forth above and using theappropriate reagents, starting materials, and purification methods knownto those skilled in the art.

Example 1

2-(Pyridin-2-ylmethyleneamino)-phenol (ARN4261)

2-Aminophenol (1.09 g, 10 mmol) was dissolved in ether (20 mL) and DCM(5 mL). 2-pyridinecaroxaldehyde (0.95 mL, 10 mmol) was added to theabove solution. The reaction mixture was stirred at room temperature for17 h; precipitate was formed. The light yellow solid (1.52 g, 77%) wasfiltered and dried. ¹H (CDCl₃) δ 8.85 (s, 1H), 8.72 (d, J=3 Hz, 1H),8.21 (d, J=9 Hz, 1H), 7.84 (t, J=7.5 Hz, 1H), 7.39 (t, J=7.5 Hz, 1H),7.31 (bs, 1H), 7.25 (t, J=9 Hz, 1H), 7.04 (d, J=6 Hz, 1H), 6.94 (t,J=7.5 Hz, 1H), MS (M+H) 199.

2-[(pyridine-2-ylmethyl)-amino]-phenol (ARN 2966)

A mixture of 2-aminophenol (12.23 g, 112 mmol) and 2-pyridinecarboxaldehyde (10.00 g, 93.4 mmol) in benzene (100 mL) was charged to a250-mL round bottom flask equipped with Dean-Stark. The mixture washeated at reflux with magnetic stirring. In this course, water wascollected and separated in the receiver by azeotropic distillation withbenzene (more benzene could be added to the flask upon necessity). Thereaction was stopped when no more water was distilled out as observed inthe Dean-Stark receiver. The mixture was cooled to ambient temperature,and solvent was then removed by rotary evaporation. This crude materialwas used as such for the next reaction without further purification.

The crude material above was dissolved in methanol (400 mL), and cooledwith an ice bath. Sodium borohydride (7.56 g, 200 mmol) was added inportions with care. After addition was complete, the mixture was allowedto warm up to room temperature and stirred for approximate 1 hr. Whenthe reaction completion was monitored by TLC, the mixture was pouredinto ice water (1 L), and extracted by TBME (3×400 mL, solid wasfiltered whenever a phase-cut was difficult). The combined organic phasewas dried over anhydrous sodium sulfate, and then filtered andconcentrated. The residual material was purified by columnchromatography on silica gel (ethyl acetate/hexanes 1:4 to 1:1), morethan 7 g of brownish solid (37% overall yield) was obtained as pureproduct (HPLC purity>99%). ¹H NMR (CDCl₃) δ 8.65 ppm (d, 1H), 7.75 ppm(t, 1H), 7.40 ppm (d, 1H), 7.30 ppm (m, 1H), 6.85 ppm (m, 2H), 6.75 ppm(m, 2H), and 4.55 ppm (s, 2H).

Assays

Compounds provided herein can be evaluated using various in vitro and invivo assays known to those skilled in the art.

Example 2 Peptide Preparation

Synthetic Aβ 1-40 peptide (sequence:AEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVV) was synthesized at the W.M.Keck Foundation Facility (Yale University, New Haven, Conn.) bysolid-phase technique on a p-methyl-benzhydrylamine resin, using aBiosearch SAM 2 synthesizer and purified by high performance liquidchromatography (HPLC) with the use of a reverse-phase support medium(Delta-Bondapak) on a 0.78×30 cm column with a 0-66% linear gradient ofacetonitrile in 0.1% (v/v) trifluroacetic acid, as previously described.The peptide content of the eluate was monitored by measurement of itsabsorption at 214 nm. To verify the sequence and purity of the peptide,linear, time-of-flight mass spectrometry was performed at the SkirballInstitute at New York University. For aggregation studies the peptidewas diluted in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP; Sigma St. Loius,Mo.) at a concentration of 10 mM/mL, aliquoted and lyophilized. HFIPtreatment renders peptides monomeric with minimal β-sheet content.Lyophilized peptides were stored at −80° C. and resuspended immediatelyprior to each experiment in the appropriate diluent.

Example 3 Aggregation Experiment

The effect of compounds of the present invention on aggregation of Aβ1-40 peptide was tested using a Thioflavin-T assay according topreviously published methods. Aggregation of Aβ 1-40 incubated alone wasmeasured for comparison. Aβ 1-40 was HFIP treated (as described above)and reconstituted in 100 mM Tris buffer (pH 7.4) to obtain a 100 μmol/Lconcentration. Stock of investigational compounds (50 mmol/L stockdiluted in DMSO) was added to Aβ 1-40 to achieve of a concentration 10or 100 μmol/L of investigational compound in 100 μmol/L of Aβ 1-40. Allincubations were performed over a period of 7 days at 37° C. and theincubation mixture was slowly mixed for 6 hours every 24 h. At theconclusion of the experiment samples containing 15 μg of Aβ 1-40 withand without investigational compounds were added to 1 mL of 50 mMglycine, pH 9.2 and 2 μM of Thioflavin-T (Sigma Chemical, Co.; St.Louis, Mo.). Fluorescence was measured at an excitation of 435 nm and anemission of 485 nm in a Perkin-Elmer LS-50B fluorescencespectrophotometer (Perkin Elmer Instruments, Shelton, Conn.). A timescan of fluorescence was performed and three values after the decayreached a plateau (280, 290, 300 seconds) were averaged. The backgroundfluorescence of 40 μL of Tris buffer added to 2 μM/L of Thioflavin-Tsolution was subtracted. Samples were run in duplicate. Differences inamount of fibrils formed in the presence of investigational compoundswere evaluated by means of one-way ANOVA followed by a Dunnet post-hoctest using Statistica (version 6.1, StatSoft Inc., OK).

Example 4 Anti-Aβ Aggregation Properties of ARN4261

Our screen yielded two initial leads ARN4261[(E)-2-(pyridin-2-ylmethylene-amino)phenol] and ARN4224 (C16H16N402;MW=296.3).

ARN4261 had stronger effect on Aβ fibrillization than ARN4224 while bothcompounds showed comparable effect on Aβ oligomerization.

As shown in FIG. 1, (A) Thioflavin-T fibrillization assay. 100 mM ofHFIP monomerized synthetic Aβ40 was incubated in 0.1M Tris pH 7.0, T=37°C. for 8 days in the presence of 0-100 μM concentration of compounds.E_(MAX) (% of maximal fibril reduction) and EC₅₀ were 88% and 16 μM forARN4261, and 55% and 44 μM for ARN4224, respectively (B) Transmissionelectron microcopy (TEM) analysis confirmed that the ARN4261treatmentmarkedly reduced density and length of Aβ fibrils. An arrow indicates Aβmonomers clustered in ill developed protofibril. (C) Oligomerizationassay. ARN4261 and ARN4224 reduced the amount of Aβ oligomers by 78% and74%, respectively p<0.001. A compound 69b (GKLVFNmgA) was used as apositive control. 69b is homologous to Aβ sequence 17-21 and containsN-methyl glycine (Nmg), which renders it capable of anti-fibrillizationand anti-oligomerization effect. (D) Principle of oligomerization assay.100 μM Aβ40 was aggregated alone or with the addition of 10 μM of testedcompounds [1:10 compound: Ab ratio] for 24 h in conditions promotingoligomers assembly, i.e., DMEM/F-12 medium+0.2% SDS, T=4° C. Prior toSDS-PAGE in non-reducing conditions samples were treated withglutaraldehyde. A strong smear of Aβ oligomers is seen between 37 and 70KDa markers (arrows) in lane 2, and a dense band below the 25 KDa markerreflects Aβ monomers non-dissociated by 10% polyacrylamide gel. Nooligomers above 37 KDa marker are seen in lane 1 containing only Aβmonomers run as a control. Lanes 3-5 show reduced amount of oligomers asa result of treatment with ARN4261, ARN4224, and 69b. (E) TEM of Aβoligomers. White arrowheads indicate oligomers in a control sampleswhereas ARN4261 treatment increased number of Aβ monomers and dimers.Yellow arrowhead indicates smaller oligomers.

Example 5 Cell Culture Neurotoxicity Studies

The effect of 0.01-100 μmol/L concentrations of investigationalcompounds was tested on the viability of the N2a murine neuroblastomacell line (American Type Culture Collection, Manassas, Va.). N2a cellswere grown in Eagle's minimal essential medium with the addition of 10%fetal bovine serum, streptomycin and gentomycin (Sigma, St. Louis, Mo.),harvested with 2% trypsin and plated at 10,000 cells/100 μL per well inflatbottom, 96-well microtiter plates. The cells were allowed to attachto the plate overnight in an incubator (37° C., 5% CO₂) and in thefollowing morning stocks of investigational compounds (50 mmol/L stockdiluted in DMSO) were added to cells to achieve the final concentration0.01-100 μmol/L. Adequate amounts of DMSO (Dimethyl sulfoxide, Sigma,St. Louis, Mo.) were added to control cells. Cells were grown in thepresence of investigational compounds for 48 h and then their viabilitywas assessed using a metabolic assay, which is based on cleavage of theyellow tetrazolium salt (MTT) to purple formazan crystals by viablecells. The MTT assay (Roche Molecular Biochemicals, Indianapolis, Ind.)was performed according to the manufacturer's instructions. The resultsfrom cell culture neurotoxicity studies were evaluated by one-wayanalysis of variance, followed by a Dunnett's test as a post hocanalysis.

As shown in FIG. 2 (MTT assay), the compounds were tested for toxicityin SK-N-SH human neuroblastoma cells using MTT cell viability and LDHrelease (membrane integrity) assays. ARN4261 showed no toxicity in0.1-100 μM concentrations, whereas 100 μM ARN4224 showed toxicity inboth MTT and LDH release assays (not shown).

Example 6 Optimization of ARN4261 Structure for In Vivo ApplicationPharmacokinetic and BBB Permeability Studies

Analysis of chemical structure stability revealed that ARN4261 is proneto self-decomposing and is easily degradable in acidic pH, hence is notsuitable for oral administration. This is because of the instability of—C═N— bond. Therefore we have synthesized a reduced version ofARN4261dubbed ARN2966 (2-[(pyridine-2-ylmethyl)-amino]-phenol, MW 200.2Da, Log P 1.96). Surprisingly, ARN2966 was found to be not toxic, and inanti-Aβ aggregation assays it behaves comparably to ARN4261.

Pharmacokinetic characterization including BBB permeability of ARN2966was performed in three months old, male CD-1 WT mice, which received asingle oral (po; 25 mg/kg) or intravenous (iv; 5 mg/kg) dose of ARN2966and were sacrificed 0.25, 0.5, 1, 2, 8, and 24 hr later (n=3 per timepoint). Plasma and brain concentration of ARN2966 were determined usingliquid chromatography-mass spectrometry (LC/MS) (Table I). ARN2966 has aserum t_(1/2) of 6.13 hr and achieved maximal brain concentration of21.4 μg/kg (0.11 μM) after iv dosing. 64.2% of its orally administereddose was absorbed from the alimentary tract. As mentioned above, ARN4261is prone to self-decomposing and is easily degradable in acidic pH, andhence is not suitable for oral administration. This is because of theinstability of —CH═N— bond. Therefore, we focused on PK/BBB permeabilitycharacterization of ARN2966, where —CH═N— bond was reduced to —CH₂—NH—.

TABLE I PK Properties of ARN 2966 Plasma Brain ARN 2966 t_(1/2) T_(max)C_(max) AUC_((0−∞)) V_(z) CL F* T_(max) C_(max) Dose hr hr μg/L μg/L*hrL/kg L/hr/kg % hr μg/kg IV - 5 mg/kg 6.13 0.25 1031 ± 440 1229.78 35.974.07 — 0.25 21.4 ± 2.7 PO - 25 mg/kg 3.59 0.50 2658 ± 382 3947.65 — —64.20 0.50 12.5 ± 2.3 Abbreviations: t_(1/2) - half-life, T_(max) -timeof occurrence for maximum drug concentration, C_(max) - maximumconcentration, AUC_((0−∞)) area under curve, V_(z)-terminal phase volumeof distribution, CL-clearance, F-fraction dose absorbed accounted fordisparity between po and iv dose difference. Data given as mean ±SD.

Example 7 ARN4261 and ARN2966 Reduce Aβ Production in Vitro

In addition to studying the effect of ARN4261 and ARN2966 on Aβoligomerization and fibrillization, we have explored their properties inrespect to the modulation of Aβ production using CHO clones stablytransfected with WT human APP751 and double Swedish APP751 mutant(KM670/671NL). The results in FIGS. 3(A) and 3(B) show inhibitory effectof ARN4261 and ARN2966 on secretion of Aβ40 and Aβ42 by 751APP_(SW) CHOcells exposed to ARN compounds for 48 hr. Values are expressed as % ofAβ40 and Aβ42 levels in conditioned media (CM) of untreated cells. FIG.3(C) Concentrations of Aβ40 and Aβ42 in 751APP_(SW)CHO cell CM underincreasing concentrations of ARN2966. 751APP_(SW)CHO cells secrete Aβ40and Aβ42 in proportions 9:1, akin to the proportions of Aβ peptidesproduced by neurons. FIG. 3(D) shows concentrations of Aβ40 in CM ofvehicle and ARN2966 treated primary hippocampal neurons derived fromTg2576 AD Tg mice. Aβ40 and Aβ42 levels were determined using sandwichELISA where C-terminal specific anti Aβ40 and Aβ42 mAbs were used ascapture Abs and biotinylated 4G8 as the detection Ab. ARN4261 inhibitedproduction of Aβ40 with IC_(50%)=0.82 μM (95% confidence interval [CI]0.76-0.88 μM) and E_(MAX)97.4±0.25%, and inhibited Aβ42 production withIC_(50%)=6.54 μM (95% CI 6.2-6.97 μM) and E_(MAX)=98.9±0.4%. ARN2966inhibited production of Aβ40 with IC_(50%)=0.81 μM (95% CI 0.74-0.89 μM)and E_(MAX)97±0.3%, while Aβ42 with IC_(50%)=5.53 μM (95% CI 3.99-7.71μM) and E_(MAX)84.5%±0.7%. We also confirmed that ARN2966 inhibitedsecretion of Aβ by primary neuronal cultures derived from Tg2576 AD Tgmice. 10 μM ARN2966 lowered concentration of Aβ40 in the conditionedmedia by 61.4% (p<0.05).

Example 8 ARN2966 Rescues M17 Neuroblastoma Cells from Death Induced byMPP+ and H₂O₂

In addition to strong effects on Aβ production, ARN2966 has been shownex vivo to confer improved viability to oxidatively challenged neuralcells (FIG. 4).

FIG. 4(A) shows increasing concentrations of ARN2966 rescue M17neuroblastoma cell death induced by MPP+ (0.5 mM1-methyl-4-phenylpyridinium,) or (B) H₂O₂ (300 μM, right panel). Cellviability was detected by MTT assay. ARN2966 treatment restored normalcell morphology as determined by phase contrast microscopy, and reactiveoxygen species (ROS) detection as studied with DCFH-DA.

Example 9 ARN2966 is not Toxic in vivo and Prevents Memory Deficit inAPP_(SW)/PS1_(dE9) AD Tg Mice

Female APP_(SW)/PS1_(dE9) mice received ARN2966 (n=10) or Vehicle (n=15)from the age of six to ten months. ARN2966 (50 mg/kg/day) was given oncea day by intraperitoneal injection. During treatment, no noticeablechanges in physical appearance, unprovoked behavior or response toexternal stimuli were observed. ARN2966-treated mice also showed properrate of age related weight gain during the treatment (FIG. 5A). Afterconclusion of the experiments, samples of organs from ARN2966 andVehicle treated animals were subjected to histopathological evaluationconducted by a veterinary pathologist. No signs of ARN2966 toxicity werereported. Signs of mild chronic peritonitis related to repeated dailyintraperitoneal compound injection, however, were reported in bothgroups.

FIG. 5.(A) shows weight of female APP_(SW)/PS1_(dE9) mice at thebeginning and end of ARN2966 treatment is similar to that of sex and agematched untreated APP_(SW)/PS1 _(dE9) mice (red); p=ns, one-tailedunpaired t-test. FIG. 5.(B) shows object recognition test results, basedon the inherent tendency of rodents to explore novel objects, are shown.ARN2966 treated APP_(SW)/PS1_(dE9) and non-Tg mice spent significantlymore time exploring the novel object while vehicle treated mice failedto distinguish between familiar and novel objects. P<0.05, unpaired,two-tailed t-test. FIG. 5.(C) shows radial Arm Maze. Mice explore8-armed labyrinth, and results are displayed as a number of errors persession. One session is given per day. During the initial three days oftesting, all animals made comparable number of errors while navigatingthrough the labyrinth. Starting from day five, vehicle treatedAPP_(SW)/PS1_(dE9)mice were consistently making more errors than ARN2966treated APP_(SW)/PS1_(dE9) and non-Tg littermates. One-way ANOVAp<0.001. Results of Newman-Keuls post-hoc analysis for days 4-10 aredisplayed on the graph.

During the last three weeks of treatment, animals were behaviorallytested using object recognition paradigm and the 8-armed radial armmaze, both of which measure memory capability. Akin to their non-Tglittermates, ARN2966 treated APP_(SW)/PS1_(dE9) mice were able todistinguish a novel object from the familiar object they were exposed toduring previous sessions (FIG. 5B). However, vehicle treatedAPP_(SW)/PS1_(dE9) mice were incapable of discriminating betweenfamiliar and novel objects, as is characteristic of their phenotype. Onthe radial arm maze, ARN2966 group made fewer errors than vehicle group,and performed comparable to the non-Tg group (FIG. 5C). These resultsindicate that ARN2966 prevents memory deficit in APP_(SW)/PS1_(dE9) miceand does not cause toxicity.

Example 10 ARN2966 Treatment Lowers Aβ Plaque Load

Female APP_(SW)/PS1_(dE9) AD double transgenic (Tg) mice received dailyintraperitoneal injections of ARN2966 (50 mg/kg) starting from the ageof six months until the age of 10 months. Shown in FIG. 6 are example,Thioflavin-S brain sections from control (A) and (B) ARN2966 treated 10month old, female APP_(SW)/PS1_(dE9) revealing an apparent difference inthe load of Aβ plaques. (C) Unbiased quantification of Aβ load revealed25.8% reduction in the Aβ load under ARN2966 treatment (p<0.01, MannWhitney U Test).

Example 11 ARN2966 Treatment Lowers Load of Aβ Plaque, and Brain AβLevel

Following the course of ARN2966 treatment, animals were sacrificed, andthe load of Thioflavin-S (Th-S) stained Aβ plaques (% of histologicalsection area covered by plaques) was quantified in the brain cortex onserial coronal sections through the rostrocaudal axis of the righthemisphere as described by us [Sadowski 2004]. The left hemisphere washomogenized (1:10 weight/volume), and aliquots of the homogenate wereused to measure the level of Aβ oligomers (Aggregated β-Amyloid ELISAKit, [Invitrogen]) or subjected to formic acid (FA) extraction todetermine total Aβ40 and Aβ42 brain levels via sandwich ELISAsdiscriminating C-terminal configuration of both peptides as described byus [Sadowski 2006]. The load of Th-S positive plaques was reduced in thebrain cortex of ARN2966 treated animals by 21.9% (p<0.001; FIGS. 6A, B),while the level of Aβ oligomers was reduced by 20.5% (p<0.05; FIG. 7C).Levels of FA extracted Aβ40 and Aβ42 were reduced by 82% (p<0.001) and56% (p<0.001; FIG. 6C).

Furthermore, we conducted an acute treatment experiment where six monthsold female APP_(SW)/PS1_(dE9) mice (n=3/group) were treated for fivedays with ARN2966 (50 mg/kg/day), Compound E (3 mg/kg/day) or Vehicleinjected intraperitoneally. Mice were killed three hours after the lastinjections. The level of soluble Aβ40 was measured in the brain aliquotsfollowing diethylamine (DEA) extraction. It was lower in ARN2966 andCompound E treated groups by 39% (p<0.05) and 60% (p<0.05) comparing tovehicle treated mice, respectively (p<0.05; FIG. 6E). Furthermore,analysis of APP, C99, and C83 level on samples of brain homogenatesubjected to SDS-PAGE and western immunoblotting showed evidentreduction of APP, C99, and C83 signal in ARN2966 treated mice (p<0.05;FIG. 6F). A modest increase in C99 and C83 signal was also seen inCompound E treated animals. These results from the acute treatmentexperiment confirm the effect of ARN2966 on APP expression and Aβproduction in vivo.

FIGS. 6.(A, B) ARN2966 treatment reduces load of Aβ plaques (n=10ARN2966, n=15 Vehicle). (B) Representative photomicrograph of Th-Sstained brain sections from vehicle and ARN2966 treated 10 month old,female APP_(SW)/PS1_(dE9)reveal a difference in the load of Aβ plaques.(C) ELISA for aggregated human Aβ, revealing significant reduction inthe Aβ-56-ligomers level in ARN2966 treated animals. (D) Reduced Aβ40and Aβ42 levels in FA extracted brain homogenate, which represent thetotal brain content of Aβ peptides in ARN2966 treated animals (ELISA).(E) Reduced soluble Aβ40 level in DEA extracted brain homogenate, ofARN2966 and Compound E treated mice (ELISA). (F) Western immunoblotdeveloped using anti-C terminal APP polyclonal Ab (1:500, Leinco, St.Louis, Mo.) demonstrating marked reduction in APP, C99, and C83 signalARN2966 treated animals. Aβ concentrations in (C) (D) and (E) are givenper gram of wet brain. All values are given as mean±SEM. Statisticalanalysis was done using two-tailed unpaired t-test, followingconfirmation of normal distribution of data using Shapiro-Wilk test.

Example 12 ARN4261 and ARN2966 Modulate APP Translation

Given that APP secretase inhibitors have encountered numerous setbacksduring clinical development, it is important to point out that ARN4261and ARN2966 do not appear to reduce Aβ production through modulatingactivity of APP secretases . As shown in FIGS. 7A, B, ARN4261 andARN2966 reduce the level of full length APP (APP FL) and both C99 andC83 APP stubs resulting from B and a secretase cleavage of APP,respectively. For comparison, we show effects of treatment withestablished γ-secretase inhibitors Compound E (Comp. E)((S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide)and Compound D (Comp. D, akaDAPT-N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butylester) which cause some accumulation of APP FL, and substantialaccumulation of C99 and C83 (FIG. 7A). Secretion of sAPP to conditionedmedia was also reduced in cells treated with ARN2966 (FIG. 7C).Immunostaining with 22C11 anti-APP mAb of 751APP_(SW) CHO cells treatedwith ARN2966 was also reduced without evidence of stainingredistribution (FIG. 7D). Pulse labeling experiment showed significantlyreduced incorporation of 35S-Methionine by APP during translation in751APP_(SW) CHO cells treated with ARN2966, while translation of β-actinremained unaltered (FIGS. 8A,B). No change in APP mRNA level wasobserved in ARN2966 treated 751APP_(SW) CHO cells (FIG. 8C). These datacollectively show a marked reduction in APP level, associated withreduced rate of APP translation, and preserved level of APP mRNA,providing solid evidence that ARN2966 is an APP translation modulator.

FIG. 7(A) shows reduced levels of full length APP (APP FL) and C99 andC83 APP stubs in cell lysates of 751APP_(SW) CHO clone treated withARN2966 or ARN4261. Treatment with γ-secretase inhibitors, Compound Eand Compound D (DAPT), modestly increased the APP FL level andsubstantially increased levels of C83 and C99 (1:500 anti-C term APPpoly. Ab, Leinco, St. Louis, Mo.). FIG. 7(B) shows reduced levels of APPFL in 751APP_(SW) CHO clone under treatment with increasingconcentration of ARN2966. Reduction in APP FL level is seen with ARN2966concentrations ≧10 μM, while no apparent change in the level of β-actinis noticed. FIG. 7(C) shows reduced levels of sAPPα (immunoblotted withmAb 6E10 1:3,000) and total sAPP stub (immunoblotted with 22C11N-terminal APP mAb; 1:1,000) in conditioned media of 751APP_(SW) CHOclone treated with ARN2966 compared to control, untreated cells.Treatment with Compound E increased level of sAPP stubs in conditionedmedia. (D) Reduced anti-APP staining (22C11 mAb against N-term. APP) in751APP_(SW) CHO cells treated with ARN2966.

FIGS. 8(A,B) shows radiolabeled APP and β-actin in 751APP_(SW) CHO cellstreated during the 2 h 35S-Methionine pulse with 25 μM ARN2966 or 10 μMComp. D. APP was immunoprecipitated with 22C11 mAb against itsN-terminus. Representative radiographs (B) and densitometric resultsaveraged from three independent experiments are shown (A). Translationof APP was reduced by 61.5% (**p<0.01) during ARN2966 treatment. FIG.8(C) shows mRNA levels for APP751_(SW) in CHO cells treated withARN4261, ARN2966, and Comp. E demonstrating lack of substantial effectof ARN compounds on APP transcription. Two sets of experiments wereconducted using either actin or GAPDH as housekeeping genes.

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From the foregoing description, various modifications and changes in thecompositions and methods provided herein will occur to those skilled inthe art. All such modifications coming within the scope of the appendedclaims are intended to be included therein.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

At least some of the chemical names of compounds of the invention asgiven and set forth in this application, may have been generated on anautomated basis by use of a commercially available chemical namingsoftware program, and have not been independently verified.Representative programs performing this function include the Lexichemnaming tool sold by Open Eye Software, Inc. and the Autonom Softwaretool sold by MDL, Inc. In the instance where the indicated chemical nameand the depicted structure differ, the depicted structure will control.

Chemical structures shown herein were prepared using ISIS®/DRAW. Anyopen valency appearing on a carbon, oxygen or nitrogen atom in thestructures herein indicates the presence of a hydrogen atom. Where achiral center exists in a structure but no specific stereochemistry isshown for the chiral center, both enantiomers associated with the chiralstructure are encompassed by the structure.

What is claimed is:
 1. A method for treating or ameliorating in a mammala medical condition selected from Alzheimer's disease, Down's syndrome,and Parkinson's disease, which comprises administering to the mammal aneffective medical condition treating amount of a compound according toformula I:

or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or acombination thereof; wherein: R₃, R₄, R₅ and R₆ are independentlyselected from the group consisting of hydrogen, halogen, substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heterocyclyl, halogen, trihalomethyl, —CN, —NO₂, —NH₂,—OR₁, —NR₁R₂, —S(O)₀₋₂R₁, —SO₂NR₁R₂, —CO₂R₁, —C(O)NR₁R₂, —N(R₁)SO₂R₂,—C(O)R₁, —N(R₁)C(O)R₂, —N(R₁)CO₂R₂, —OC(O)NR₁R₂, —OC(O)R₁, andoptionally substituted lower alkyl; R₁ and R₂ are independently selectedfrom the group consisting of hydrogen, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocyclyl, and optionally substituted lower alkyl; R is selected fromthe group consisting of hydrogen, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocyclyl, —S(O)₀₋₂R₁, —SO₂NR₁R₂, —CO₂R₁, —C(O)NR₁R₂, —N(R₁)SO₂R₂,—N(R₁)C(O)R₂, —N(R₁)CO₂R₂, —C(O)R₁, and optionally substituted loweralkyl; R′ is selected from the group having formula II:

wherein the subscript m is 1, 2, 3, or 4; the subscript n is 0, 1, 2, or3; R′″ is selected from the group consisting of hydrogen, halogen,substituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocyclyl, halogen, trihalomethyl, —CN, —NO₂, —NH₂,—OR₁, —NR₁R₂, —S(O)₀₋₂R₁, —SO₂NR₁R₂, —CO₂R₁, —C(O)NR₁R₂, —N(R₁)SO₂R₂,—C(O)R₁, —N(R₁)C(O)R₂, —N(R₁)CO₂R₂, OC(O)NR₁R₂, —OC(O)R₁, and optionallysubstituted lower alkyl; R″ is H or substituted or unsubstituted C₁₋₈alkyl or substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocyclyl, trihalomethyl, or selected from the group having formulaIII:

wherein R_(a) is selected from the group consisting of hydrogen,halogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl; and whereinthe medical condition is a neurological disorder.
 2. The methodaccording to claim 1; wherein the compound is according to formula IVaor IVb:

or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or acombination thereof; and wherein R, R_(a), R″, R″′, R₃, R₄, R₅, R₆, m orn are as in claim
 1. 3. The method according to claim 1; wherein R″′ isH.
 4. The method according to claim 1; wherein R_(a) is H or Me.
 5. Themethod according to claim 1; wherein R₃ is H.
 6. The method according toclaim 1; wherein R₄ is H.
 7. The method according to claim 1; wherein R₅is H.
 8. The method according to claim 1; wherein R₆ is H.
 9. The methodaccording to claim 1; wherein the compound is according to formula V:

or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or acombination thereof.
 10. A method for treating or ameliorating in amammal a medical condition selected from Alzheimer's disease, Down'ssyndrome, and Parkinson's disease, which comprises administering to themammal an effective medical condition treating amount of a compoundaccording to formula V:

or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or acombination thereof.
 11. The method according to claim 1, wherein themedical condition is associated with modulation of Aβ production. 12.The method according to claim 1, wherein the medical condition isassociated with inhibition of Aβ production.
 13. The method according toclaim 1, wherein the medical condition is associated with modulation ofAPP expression or APP translation.
 14. A method for lowering the load ofAβ plaque, which comprises administering to the mammal an effectivetreating amount of a compound according to formula I of claim
 1. 15. Amethod for lowering the brain Aβ level, which comprises administering tothe mammal an effective treating amount of a compound according toformula I of claim
 1. 16. A method for lowering the load of Aβ plaque,which comprises administering to the mammal an effective treating amountof a compound according to formula IVa or IVb of claim
 2. 17. A methodfor lowering the load of Aβ plaque, which comprises administering to themammal an effective treating amount of a compound according to formula Vof claim
 9. 18. A method for lowering the brain Aβ level, whichcomprises administering to the mammal an effective treating amount of acompound according to formula IVa or IVb of claim
 2. 19. A method forlowering the brain Aβ level, which comprises administering to the mammalan effective treating amount of a compound according to formula V ofclaim 9.